Abstract
BackgroundThe sleep sequence: i) non-REM sleep, ii) REM sleep, and iii) wakefulness, is stable and widely preserved in mammals, but the underlying mechanisms are unknown. It has been shown that this sequence is disrupted by sudden REM sleep onset during active wakefulness (i.e., narcolepsy) in orexin-deficient mutant animals. Phospholipase C (PLC) mediates the signaling of numerous metabotropic receptors, including orexin receptors. Among the several PLC subtypes, the β4 subtype is uniquely localized in the geniculate nucleus of thalamus which is hypothesized to have a critical role in the transition and maintenance of sleep stages. In fact, we have reported irregular theta wave frequency during REM sleep in PLC-β4-deficient mutant (PLC-β4−/−) mice. Daily behavioral phenotypes and metabotropic receptors involved have not been analyzed in detail in PLC-β4−/− mice, however.Methodology/Principal FindingsTherefore, we analyzed 24-h sleep electroencephalogram in PLC-β4−/− mice. PLC-β4−/− mice exhibited normal non-REM sleep both during the day and nighttime. PLC-β4−/− mice, however, exhibited increased REM sleep during the night, their active period. Also, their sleep was fragmented with unusual wake-to-REM sleep transitions, both during the day and nighttime. In addition, PLC-β4−/− mice reduced ultradian body temperature rhythms and elevated body temperatures during the daytime, but had normal homeothermal response to acute shifts in ambient temperatures (22°C–4°C). Within the most likely brain areas to produce these behavioral phenotypes, we found that, not orexin, but group-1 metabotropic glutamate receptor (mGluR)-mediated Ca2+ mobilization was significantly reduced in the dorsal lateral geniculate nucleus (LGNd) of PLC-β4−/− mice. Voltage clamp recordings revealed that group-1 mGluR-mediated currents in LGNd relay neurons (inward in wild-type mice) were outward in PLC-β4−/− mice.Conclusions/SignificanceThese lines of evidence indicate that impaired LGNd relay, possibly mediated via group-1 mGluR, may underlie irregular sleep sequences and ultradian body temperature rhythms in PLC-β4−/− mice.
Highlights
The behavioral state of sleep consists of two basic stages: (1) rapideye-movement (REM) sleep with typical theta electroencephalogram (EEG) waves and (2) restful non-REM sleep, with slow EEG waves
In Phospholipase C (PLC)-b42/2 mice, episodes of REM sleep interrupted by wakefulness frequently were immediately followed by another REM episode, creating an unusual sleep sequence with REMsleep/wakefulness repeats (Fig. 1B,C)
Sets of more than 3 REM sleep/wakefulness repeats (Fig. 1B), occurred only in PLC-b42/2 mice both during the day (6.060.6 sets, n = 6) and the night (6.561.5 sets, n = 6). These results clearly demonstrate that the mechanism underlying the progression of the proper sleep sequence is impaired in PLC-b42/2 mice
Summary
The behavioral state of sleep consists of two basic stages: (1) rapideye-movement (REM) sleep with typical theta electroencephalogram (EEG) waves and (2) restful non-REM sleep, with slow EEG waves. The sleep sequence: i) non-REM sleep, ii) REM sleep, and iii) wakefulness, is stable and widely preserved in mammals, with REM sleep consistently following non-REM sleep. Narcolepsy is characterized by sudden REM sleep attacks during active wakefulness, and represents a rare condition in which the preserved sleep sequence is disrupted. Orexin receptor mutations are the cause of canine narcolepsy [3], and orexin knockout mice displayed behaviors resembling aspects of narcolepsy [4,5,6], suggesting that orexinergic neuronal transmission is an essential component of the preserved sleep sequence. The sleep sequence: i) non-REM sleep, ii) REM sleep, and iii) wakefulness, is stable and widely preserved in mammals, but the underlying mechanisms are unknown. It has been shown that this sequence is disrupted by sudden REM sleep onset during active wakefulness (i.e., narcolepsy) in orexin-deficient mutant animals. Behavioral phenotypes and metabotropic receptors involved have not been analyzed in detail in PLC-b42/2 mice,
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